Ferromagnetic contrast media and method of use

ABSTRACT

Ferromagnetic contrast media incorporating magnetic ferrites such as magnesium ferrite, barium ferrite, manganese ferrite, manganese-zinc ferrite, nickel ferrite, magnetite, or ferromagnetic garnets; gamma -ferric oxide and a guar gum stabilizer. Such media are used for diagnostic or therapeutic treatments of the gastrointestinal or lymph tracts, by subjecting the patient to external magnetic fields to concentrate the medium in the body region to be diagnosed or treated.

United States Patent l 13,592,l85

[72] [mentors Ephnlmltl'rd: 3,235,46l 2/1966 Habichtetal [67/95 Eh'orncunmbolh flhho hd rl l 3,356,575 l2/[967 Arbaeusetal [67/95 Apr. [8,1967 July [3, I97 I Yeda Research and Development (20., Ltd. ltehovoth,[Ind [21 I Appl. No. [22] Filed [45) Patented [73) Assignee [54]IERROMAGNETIC CONTRAST MEDIA AND METHOD OF USE 4 Claims. No Drawings[52] US. Cl it [28/2, [28/260, 424/4, 424/[58 [5!] lnt.C[ ..A6lk27/08[50] Field 0! Search [67/55, 95, 84.5; 424/4; [28/260, 2 R

[56] References Cited UNITED STATES PATENTS 2,67l,45l 3/1954 Bolger[67/95 X OTHER REFERENCES Bozorth, Ferromagnetism," D, Van Mostrand Co.,New York,( [95 pp, 244- 249.

JAMA, Vol. [95, No. ll, p. 28- 29 [966) Husa' s PharmaceuticalDispensing, Eric Martin et a[ Mack Publishing Co., Easton, Pa. [959)Primary ExaminerA[bert T. Meyers Assistant Examiner-Vera C. ClarkeAtrorney-0strolenk, Faber, Gerb and Soffen ABSTRACT: Ferromagneticcontrast media incorporating magnetic ferrites such as magnesiumferrite, barium ferrite, manganese ferrite, manganese-zinc ferrite,nickel ferrite, magnetite, or ferromagnetic garnets; -ferric oxide and aguar gum stabilizer Such media are used for diagnostic or therapeutictreatments of the gastrointestinal or lymph tracts, by subjecting thepatient to external magnetic fields to concentrate the medium in thebody region to be diagnosed or treated.

FERROMAGNETIC CONTRAST MEDIA AND METHOD OF USE This invention relates toimproved ferromagnetic contrast media, and more particularly to a methodfor the diagnostic and/or therapeutic administration of such media.

It is well known to employ barium sulfate as a contrast material in thegastrointestinal tract. The ingestion of "barium meals" (slurries ofbarium sulfate in water, with or without a stabilizing agent) provides avaluable diagnostic tool, enabling radiological investigation of thestomach and intestines, examination of contractions and movements, anddetermination of the location and size of ulcers and growths. Similarly.the use of barium enemas facilitates radiological detection of theexistence and location of growths along the colon.

The use of barium contrast media, while relatively simple, is not freefrom complication. Misinterpretation may arise due to the presence inthe region opacified of food remnants, feces, and air bubbles, which aresometimes difficult to distinguish from tumors. In some cases as, forexample, in the duodenum, the barium compound passes rapidly, makingdiagnosis quite difficult. Moreover, the radiologist has practically nocontrol over the internal diffusion of the barium compound, despite thefrequent desirability or necessity to concentrate the contrast medium inregions to which it might not naturally diffuse. In such instances, theradiologist has been compelled to selectively apply pressure to theabdomen and tilt the examination table to vary the patients orientationas may be desirable.

The use of barium sulfate contrast media additionally poses problems asto patient acceptability, Thus, frequent variation of the patient'sorientation as may be required in connection with barium therapy, mayresult in disorientation and even nausea of the patient during diagnosisor treatment. Additionally, the chalky taste of barium contrast mediafurther complicates their use in human diagnosis or therapy.

The use of magnetic particles as contrast or therapeutic media haspreviously been proposed in, for example, the fol lowing publications:Magnetism in Medicine," "Journal of Applied Physics," Vol. 3|, No. 5(May, I960), pages 404s- 405s; Experimental Approach in the Use andMagnetic Control of Metallic lron Particles in the Lymphatic andVascular System of Dogs as a Contrast and Isotopic Agent," AmericanJournal of Radiology, Vol. 90, No. 5 (Nov. 1963), pages 1068-I077;Magnet Attracts iron to Thrombose Aneurysms, Journal of theAmerican Medical Association, Vol. 195, No. ll (Mar. I4, 1966), pages28-29; Particles Iron Out Cranial Aneurysm, Medical World News (May 27,I966), pages 30--3 l.

The preceding literature refers to the use ofiron particles as contrastmedia or as therapeutic agents employed to thrombose intracranialaneurysms. Such iron particles are not, however, fully inert within apatients body and, moreover, possess relatively high densities,necessitating the administration of relatively large quantities byweight to achieve a desired opacifying function.

It is accordingly among the objects of the present invention to providenovel contrast media, and a method for the diagnostic and/or therapeuticadministration of same, which may be readily administered and accuratelyemployed to opacify and predetermined body region.

A further object of the invention is to provide such a medium which isferromagnetic in nature and which may thus be administered to a patientand thereafter subjected to a magnetic field applied externally of thepatient's body to facilitate its concentration in any portion of thebody.

It is yet a further object of the invention to provide such a contrastmedium which is chemically inert to body fluids and tissue and whichpossesses a density such that relatively small quantities by weight ofthe material are required to produce adequate contrast ofdesired bodyorgans.

These and other objects and advantages of the present in vention will bemore fully apparent from a consideration of the following detaileddescription of preferred embodiments of the ferromagnetic contrastmedium and diagnostic and/or therapeutic method hereof.

We have found that improved diagnostic and/or therapeutic results may beachieved by administering to the patient to be treated a ferromagneticcontrast medium incorporating a magnetic ferrite having a particle sizeof 50 microns or less and exhibiting a remanence magnetizationapproaching, and nearly approximating, saturization magnetization valuesof from about 30 to e.m.u. Upon the administration of such acomposition, the patient may be subjected to an externally appliedmagnetic field to concentrate the composition in the particular bodyorgan or cavity to be diagnosed or treated.

The ferromagnetic contrast media hereof may thus be concentrated ingiven portions of, for example, the gastrointestinal or lymph tracts,without continually shifting the orientation of the patient or thetreatment table. Moreover, it is possible to utilize the contrastmaterial hereof to differentiate, for example, between air bubbles orfeces and polyps by initially moving the magnetic contrast materialrelative to such objects, and thereafter moving the entire mass. Uponfluoroscopic examination employing such technique, polyps would appearstationary whereas air bubbles or feces would move.

Use of ferromagnetic contrast media of the present inventionadditionally facilitates the development of new therapeutic techniques.Thus, it is possible to treat ulcers by covering the same for prolongedperiods with compositions containing such magnetic media; suchcompositions may additionally contain suitable medicaments such asmagnesium hydroxide, currently employed in ulcer therapy.

It has been found that the novel contrast media of this inventionpossess several specific advantageous properties, in addition tofacilitating the improvements referred to hereinabove, Thus, the ferritematerials employed in accordance herewith are sufficientlyferromagnetic, exhibiting saturation magnetizations of from about 30 to80 e.m.u., to facilitate effective concentration of the same by means ofan externally applied magnetic field or fields. Secondly, such materialshave been found to absorb X-rays for diagnostic purposes, and to adhereto the walls of, for example, the stomach and intestines withoutclumping of flocculating. Moreover, the ferrite materials may beprovided in extremely fine size ranges of 50 microns or lessermagnitudes.

Additionally, only small amounts of the ferrite contrast media hereofare required to satisfactorily effect any particularly desired contrastfunction. Thus, in some cases, only about grams of ferrite would besuspended in [50 cc. of water to facilitate examination of the humanstomach. On the other hand, and as indicated above, it is presentlynecessary to utilize, for example, about 200 grams of barium sulfate fora suspension to fill the human stomach to effect X-ray examinationthereof.

The magnetic ferrites so utilized are ferromagnetic ceramic oxidescontaining two magnetic lattices which are opposed to one another butwhich do not cancel each other out. Ferrites which may be employed ascontrast media include magnesium ferrite, barium ferrite, manganeseferrite, manganese-zinc ferrite, magnesium-zinc ferrite, nickel ferrite,magnetite, and the ferromagnetic garnets. Other ferrites, e.g., cadmium,zinc and copper ferrite, are not so suitable in that they are notsufficiently magnetic, viz, do not possess a high enough magnetizationof 30 e.m.u., per gram, at body temperature to permit control bymagnetic fields.

It is preferred to employ magnesium ferrite (MgFe O, as a contrastmedium for diagnostic and/or therapeutic examination of thegastrointestinal tract. Such material crystallizes with a spinelstructure after preparation by sintering at temperatures between l,0OOand l,300 C. It is substantially insoluable in either water orhydrochloric acid at body temperatures and can be milled into particleshaving grain sizes similar to the commercially available barium sulfatematerials, i.e., from about 1 to 50 microns.

The magnetization of magnesium ferrite is dependent upon its mode ofpreparation and quenching. With air quenching, the materials are takenout of the oven and left to cool at room temperature in the containersthey were fired in, and attain a saturation magnetization of 30-40e.m.u. per gram, depending on firing temperature and percent excess MgOin the material. With ice water quenching, the sample is taken out ofthe oven very quickly and dumped out of the hot container and into anice bath. A saturation magnetization of up to 60 e.m.u. per gram may beattained in this manner.

While it is thus desirable to utilize a quenched magnesium ferrite inthe practice of the present invention (since the magnetization of suchmaterial is substantially greater than that of the correspondingunquenched ferrite), other ferrites need not be necessarily so treated.Thus, while magnesium-zinc ferrites, e.g., one in which about percentzinc is incorporated, possess saturation magnetizations of 59 e.m.u. pergram if quenched after firing, such ferrites possess saturationmagnetizations of as much as 48 e.n.u. per gram when prepared withoutquenching.

Magnesium ferrite is particularly acceptable for oral consumption, asits color varies from orange-brown to a darkbrown, depending upon itsmode of preparation. On the other hand, other magnetic ferrites areblack and may thus be less acceptable for patient administration.Moreover, unlike barium sulfate, the oral administration of magnesiumferrite in, for example, an aqueous slurry, leaves no after-taste and isthus particularly suitable for use as an X-ray contrast medium.

it is believed that the magnesium ferrite, when so administered, coatsthe mucosa of the gastrointestinal tract, the coating comprising amaterial of the formula (MgO),MgFe 0,, which does not agglomerate, whichmay readily be concentrated by magnetic force, and which is readilyX-ray absorptive. It will, however, be understood that the presentinvention is not restricted to the preceding proposed mechanismofoperation,

In one particular instance, i.e., for diagnostic and/or therapeutictreatment of the lymph tract, it is preferred to em ploy as the contrastmedium the so-called ferromagnetic garnets. Such materials may bereadily sized into extremely fine particles, i.e., having particle sizesof from (H to 10 microns. It has been found that the use of aferromagnetic contrast medium possessing such a particle size range isimportant to effect satisfactory X-ray examination of the lymph tract.

The magnetic ferrite contrast material of the present invention may beadministered together with other known adjuvants employed in connectionwith barium contrast media. It is, however, desirable, particularly inthe case of the preferred magnesium ferrite material, to admix the samewith 'yferric oxide. The 'y-ferric oxide is admixed with the magnesiumferrite in amounts of up to 60 percent by weight of the mixture toincrease the saturation magnetization of the latter material and therebyfacilitate improved concentration of the same by an externally appliedmagnetic field. The y-ferric oxide is substantially inert, dissolvingonly slightly in hydrochloric acid at a pH of l and at bodytemperatures. The mixture of magnesium ferrite and -y-ferric oxide inthe amounts specified above, viz, in proportions of up to about 60percent by weight of the mixture, may possess a saturation magnetizationof up to 80 e.m.u. per gram, generally from about 45 to 70 e.m.u. pergram.

Preferably, the magnesium ferrite or other ferrite contrast medium isorally administered in aqueous suspension. It has been determined thatstable suspensions of such materials may be produced by admixing theferrite composition with a Guar gum stabilizing agent, other knownstabilizers such as pectin, carboxy methyl cellulose and sodium alginatenot being so effective. Guar gum, which is recognized as a safe foodadditive, consists of the ground endosperms of the Guar bean (leguminousseed Cyamopsis tetragonolobus), the water-soluble fraction of which (85percentl primarily comprises mannose and galactose, It is suitablyadmixed with the magnesium or other ferrite in amounts of from about lpercent to Zpercent by weight ofthe mixture.

it is additionally desirable to admix the magnesium ferrite contrastagent with magnesium oxide for ulcer therapy applications. The magnesiumoxide, a recognized medicament in ulcer treatment, forms a solidsolution with magnesium ferrite when such materials are prepared inadmixture by sintering at temperatures of about l,0O0C. The magnesiumoxide may be employed in amounts of from about 10 percent to lOO percentby weight of the magnesium ferrite material. Use oflesser proportions ofthe magnesium oxide, preferably about [0 percent has been found toincrease the magnetization of the ferrite. The addition of greaterproportions of the magnesium oxide, e.g., amounts of the order of 50percent or greater, lowers the magnetization but markedly improves thetexture of the ferrite composition and lightens its color to facilitateimproved patient acceptance.

The following examples illustrate preferred, nonlimiting embodiments ofthe X-ray contrast media, and the diagnostic and/or therapeutic methodof administering such media, of the present invention:

EXAMPLE 1 A magnesium ferrite was prepared by filling each of the twojars ofa ball mill with N9 grams of ferric oxide, 62.9 grams ofmagnesium carbonate, 560 ml. water, 25 porcelain porcelain balls 19 mm.in diameter, and 20 porcelain balls l2 mm. in diameter. The mixture wasmilled at 50 r.p.m. for 3 hours, after which the material from both jarswas emptied into a Buchner funnel and most of the water extractedtherefrom. The material was thereafter dried in a suitable porcelaincontainer placed in an oven for 15 hours at l50 C.

The ferrite was prepared by a prefiring operation conducted for 2 hoursin a furnace heated at l,000 C. in an oxygen atmosphere. Whileconventional magnesium ferrite compositions are thereafter subjected toa firing operation at between ]200 C. and 1350 C., such darkens thecolor of the composition to a black or brown-black hue. The prefiredmagnesium ferrite, on the other hand, had a less objectionablereddishbrown color. Accordingly, although the magnetization of thepreflred material was only about 27 e.m.u. per gram as compared with a36 e.m.u. per gram magnetization attainable after firing of thecomposition, the former material was preferred.

The magnesium ferrite contrast material was placed in an aqueoussuspension containing a y-ferric oxide magnetization adjuvant. 245 gramsof the magnesium ferrite were thus admixed with 250 grams of they-ferric oxide to produce about 1,000 cc. of the desired aqueoussuspension.

Fifty or cc. doses of the aqueous suspension were orally administered tohuman patients. The patients were subjected to radiological examinationapproximately 5 minutes after ingesting the contrast medium.

A permanent magnet was simultaneously moved across each patient'sabdomen during irradiation to determine the effects of the same upon thecontrast material in the gastrointestinal tract. The magnetic ferriteproduced opacification on the fluoroscope and on X-ray film in the samemanner as characteristic of barium sulfate. Moreover, it was found thatmovement of the externally applied magnet effected concentration of theferrite material in predetermined portions of the gastrointestinalregion.

EXAMPLE 2 A contrast material similar to that utilized in Example l wasprepared, employing twice the stoichiometric amount of magnesiumcarbonate set forth in the preceding example. Upon reacting theferrite-forming constituents in the manner set forth above, a materialwas produced containing MgO dissolved in the ferrite which, whensuspended in the aqueous medium, provided a distinctly basic reaction bythe formation of Mg(OH),. Such composition, when administered in themanner described in Example I, produced like X-ray opacification andcould, moreover, be utilized in connection with ulcer therapy.

EXAMPLE3 A mixture of 8 grams of a commercially available barium sulfateformulation (available under the trade designation Barotrast" andcomprising barium sulfate plus an emulsifier) and 6.4 grams of powderedmanganese-zinc ferrite (Mn,Zn, ,Fe,0.. wherein it was about 0.5) wereinitially mixed by hand and 25 cc. of milk were thereafter added theretowith agitation. Finally. the mixture was ball milled for about minutes.A stable suspension of the ferrite was thus produced from which thesolids did not separate by gravity or by magnetic at traction.

The contrast material was administered to a number of test guinea pigsby inserting a flexible tube through each animal's mouth into itsstomach and passing from 5 to It) cc. of the contrast material thereto.Each test animal was thereafter fluoroscoped approximately l hour afteradministration ofthc contrast medium, the test magnet being passed overthe abdomen and sides of the animal simultaneous with X-ray irradiationto determine the effect of the magnetic field thus produced upon thecontrast material in the gastrointestinal tract.

Two permanent magnets were thus employed. The first such magnet was astrong horseshoe type magnet having a 2 cm. wide gap. and a maximumfield strength within the gap of L7 kilo-oersted. The field strengthsome 2 cm. away from the gap along the perpendicular to the center ofits face was approximately (L4 kilo oersted. which corresponded to thefield strength produced within the test animals during the experiments.The second magnet was substantially a half disc in shape, 7 cm. indiameter. 2 cm. thick. and magnetized along the axis of a cylinder fromwhich the half disc was cut. Such magnet produced a field strength ofabout 0.4 kilo-(worsted l cm. from either flat face.

Employing the preceding magnet elements, it was found possible to movethe contrast material through the stomach of each test animal to effectconcentration of the medium adjacent to one side of the animal inproximity to the magnet. It was additionally possible, by placing ahorseshoe magnet against the animal's side. to pull its small intestinebetween the pole pieces of the magnet. Movement of such magnet along theanimal: side caused the adjacent sections of the intestine to follow themagnet, removal of the same resulting in an apparent unfolding of theintestinal sections and return of the same to their normal relation.Such operation could, and was. repeated several times duringfluoroscopic examination.

One test animal was sacrificed and operated upon to determine whethersny particles of the contrast medium had penetrated the wall of thesmall intestine sections which had been subjected to the greatestmagnetic force. In these histological examinations. no ferrite particleswere found to have penetrated the intestines. stomach or liver of thetest animal.

A further test animal was sacrificed and operated upon after having theflat permanent magnet taped to its side for 2 hours. It was found thatthe meal which had been fed to the animal remained primarily within itsstomach. solely a small portion of the contrast medium having reachedthe upper section of the duodenum. Such section of the duodenum had beenatrscted to the magnet. which prevented the material from moving on.thereby blocking the passage. Here. too. no ferrite particles were founddeeper than the intestinal surface.

It was found. in both test animals sacrificed. that the contrastmaterial remaining within the stomach had a pH of 3 whereas thatremaining within the intestine had a pH of 8. Both such material samplesappeared to have the same consistency as prior to feeding.

The following examples set forth the composition of further contrastmedia incorporating a guar gum stabilizer (Example 4 and illustratingthe manner in which the saturation magnetization of the ferrite contrastmaterial may be modified by variation in the method of preparationthereof (Examples EXAMPLE 4 A contrast medium similar to that formulatedin Example I was prepared. The contrast medium incorporated 245 grams ofthe magnesium ferrite prepared as described in such example. 250 gramsof the y-ferric oxide and 10 grams of a guar gum stabilizer. in about 1liter of aqueous suspension.

EXAMPLE 5 EXAMPLEb A material with 30 percent excess MgO was prepared bymixing 676 grams MgCO, with I038 grams Fe,O,and 5 liters of water. Itwas fired for 6 hours at 1000C. and quenched in an ice water bath. asdescribed above. The magnesium ferrite composition attained a saturationmagnetization of $3 e.m.u. per gram.

EXAMPLE 7 A material with ID percent excess MgO was prepared by mixing37l grams MgCO with 639 grams Fqo and 4.5 liters water. It was fired atll00 C. for 5 hours and ice water quenched as described above. Themagnesium ferrite composition attained a saturation magnetization of 58e.m.u. per gram.

What we claim is:

I. A method for X-ray visualization gastrointestinal tract of a patient,which comprises:

a. orally administering or administering by enema to the patient acontrast medium comprising an aqueous suspension of a magnetic ferriteconsisting of a ferromagnetic ceramic oxide containing two magneticlattices which are opposed to one another but which do not cancel eachother out. said magnetic ferrite having a particle size of no more than50 microns and exhibiting a saturation magnetization of from about 30 toe.m.u. per gram. and the contrast medium containing ofthe order of I00grams of said ferrite per dose;

b. applying an external magnetic field in the region of the patient:gastrointestinal tract to affect the disposition of the contrast mediumtherein; and

e. detecting the presence of said contrast medium in thegastrointestinal tract by X-ray examination.

2. The method as defined in claim I. in which said magnetic ferrite isselected from the group consisting of magnesium ferrite. magnesium-zincferrite. barium ferrite. manganese ferrite. manganese-zinc ferrite.nickel ferrite. magnetite and ferromagnetic garnets.

3. An aqueous suspension of a magnetic ferrite and a guar gumstabilizer. the ferrite consisting of a ferromagnetic ceramic oxidecontaining two magnetic lattices which are opposed to one another butwhich do not cancel each other out. having a particle size of no morethan 50 microns. and exhibiting a saturation magnetization of from about30 to 80 e.m.u. per gram; and the suspension incorporating the ferritein an amount of about I00 grams per cc. of the aqueous medium and thestabilizer in an amount of from 1 percent to 2 percent by welghtthereof.

4. The aqueous suspension of claim 3, wherein said ferrite is selectedfrom the group consisting of magnesium ferrite. magneslum-zlnc ferrlte.barium ferrite. manganese ferrite. manganese-zinc ferrite. nickelferrite, magnetite and ferromagnetic garnets.

2. The method as defined in claim 1, in which said magnetic ferrite isselected from the group consisting of magnesium ferrite, magnesium-zincferrite, barium ferrite, manganese ferrite, manganese-zinc ferrite,nickel ferrite, magnetite and ferromagnetic garnets.
 3. An aqueoussuspension of a magnetic ferrite and a guar gum stabilizer, the ferriteconsisting of a ferromagnetic ceramic oxide containing two magneticlattices which are opposed to one another but which do not cancel eachother out, having a particle size of no more than 50 microns, andexhibiting a saturation magnetization of from about 30 to 80 e.m.u. pergram; and the suspension incorporating the ferrite in an amount of about100 grams per 150 cc. of the aqueous medium and the stabilizer in anamount of from 1 percent to 2 percent by weight thereof.
 4. The aqueoussuspension of claim 3, wherein said ferrite is selected from the groupconsisting of magnesium ferrite, magnesium-zinc ferrite, barium ferrite,manganese ferrite, manganese-zinc ferrite, nickel ferrite, magnetite andferromagnetic garnets.